The functions of plexins and their ligands, semaphorins, have been extensively studied in the central nervous system (CNS). They represent two large families of molecules that can transduce signals essential for the regulation of neuronal repulsion and attraction, cell shape, motility and cell-cell interactions (Kruger et al., 2005; Tran et al., 2007). In addition to their roles in the CNS, the diverse functions of plexins and semaphorins have also been identified in cardiac development (Toyofuku et al., 2004), vascularization and angiogenesis (Gu et al., 2003a; Serini et al., 2003), and tumorigenesis (Neufeld and Kessler, 2008; Sierra et al., 2008). More recent data strongly indicate a role for these molecules in the immune system (Kikutani and Kumanogoh, 2003; Suzuki et al., 2008). For example, plexin-A1 is expressed by dendritic cells (DCs) and regulates DC interaction with T cells to affect adaptive immunity (Takegahara et al., 2006; Wong et al., 2003). Plexin-C1 is also found on DCs, although its role is less defined and it only mildly affects T cell activation (Walzer et al., 2005). A further paper showed the high expression of plexin-D1 in double-positive (DP) thymocytes and a role for this protein in the control of intrathymic migration of these cells from the cortical to medullary region (Choi et al., 2008). Therefore, plexins are involved in diverse functions in the immune system.
Plexin-A4 belongs to the plexin A-type group (Kruger et al., 2005) and serves as a guidance cue molecule in sensory and sympathetic neurons (Waimey et al., 2008; Yaron et al., 2005) and hippocampal mossy fibers (Suto et al., 2007). One study identified plexin-A4 as a negative regulator in T cell activation (Yamamoto et al., 2008). T cells lacking plexin-A4 (Plxna4−/−) exhibited hyperproliferative responses upon stimulations in vivo and in vitro. In addition, Plxna4−/− mice developed exacerbated experimental autoimmune encephalomyelitis (EAE) when immunized with myelin oligodendrocyte glycoprotein (MOG)-derived peptides. However, given the much higher expression of plexin-A4 in myeloid cells relative to lymphoid cells (Yamamoto et al., 2008), the role of plexin-A4 in cells of myeloid lineage such as macrophages and DCs needed to be elucidated.
The innate immune system constitutes the first line of defense by rapidly detecting invading pathogens and nonmicrobial danger signals through the pattern recognition receptors (PRRs). Several classes of PRRs have been identified; the best-characterized are the Toll-like receptors (TLRs) (Iwasaki and Medzhitov, 2004). TLR family members are localized either on the cell surface (TLRs 1, 2, 4, 5 and 6) or in endosomal compartments (TLRs 3, 7, 8, 9) to detect a multitude of pathogen-associated molecular patterns (PAMPs) (Akira et al., 2006; Iwasaki and Medzhitov, 2004). TLR activation leads to the direct interactions of the TLR toll-interleukin 1 receptor (TIR) domain with a cytoplasmic TIR-containing adaptive molecule such as Myd88, TRIF, TRAM or TIRAP. Activation of Myd88-dependent signaling pathway results in the activation of IRAK kinases, the ubiquitin ligase TRAF6, TAK1 kinase complex, NF-κB transcription factor, and mitogen-activated protein kinases (MAPKs) (Akira and Takeda, 2004; Akira et al., 2006; Iwasaki and Medzhitov, 2004). TRIF-dependent type I interferon (IFN) requires a cascade involving the adaptor TRAF3, the kinase TBK1, the inhibitor of κB kinase ε (IKKε), and the transcription factor interferon-regulatory factor 3 (IRF3) (Akira et al., 2006; Kawai and Akira, 2006).
The present invention addresses the shortcomings in the art by providing methods and compositions for the treatment of immune related and inflammatory disorders and diseases based on new therapeutic targets.